The hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is the production of antibodies that bind to normal tissues (autoantibodies) and, as a result are deposited in multiple organ systems in the body, resulting in inflammation and tissue destruction. Although healthy individuals have the potential to produce autoantibodies, they do not, suggesting that autoantibody producing cells are silenced by a mechanism called tolerance. Most of our understanding of the pathogenesis of autoimmune diseases such as SLE to date has come from the studies of animal models. One such model is the hybrid mouse of New Zealand Black (NZB) x White (NZW) which develop a disease that resembles human SLE. Multiple genes contribute to the pathogenesis of autoimmune diseases such as SLE in humans. Likewise, three major regions of the genome (named Sle1, Sle2 and Sle3/Sle5) containing the genes that contribute to the disease process were identified in this SLE mouse model. Mice containing each of these genomic intervals give rise to different component phenotypes (manifestations) such as autoantibody production, kidney pathology etc., while their interaction culminates in full-blown SLE. It is not well understood how these lupus susceptibility genes are altering B cell tolerance, allowing autoantibody production. Using mouse models producing a high frequency of defined, autoreactive B cells, in the current grant application we propose to study how each of these lupus susceptibility loci influence B cell tolerance and autoantibody production leading to the development of autoimmune disease SLE. This will allow us to identify the defective tolerance processes causing the disease. Subsequently, once the genes in these genomic intervals are identified, we can study how the products of these genes specifically alter the functioning of the identified B cell tolerance processes. Such a mechanistic understanding will allow novel diagnostic and therapeutic approaches for systemic autoimmune diseases to be developed.